The authors concluded that for advanced colorectal cancer patients with wild-type KRAS there were clear benefits of anti-EGFR therapy in the third line and in the first and second line when used alongside infusional 5-fluorouracil based regimens. The conclusions are reliable but potential reviewer error and bias should be borne in mind.

To assess the effects of anti-EGFR monoclonal antibodies (MAbs) therapy in advanced colorectal cancer.

MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), clinical trial registers such as PDQ and ClinicalTrials.gov and five relevant conference proceedings were searched. Reference lists of included trials and related reviews were handsearched. Experts in the field were contacted.

Randomised controlled trials (RCTs) that compared standard treatments with or without anti-EGFR MAbs in patients (of any age) with advanced colorectal cancer were eligible for inclusion. Trials with bevacizumab on both arms were included. The primary outcome measure was progression-free survival. Secondary outcome measures were overall survival and best overall response rates.

The median age of patients ranged from 61 to 63 years and from 54% to 66% were men. Anti-EGRF antibodies included cetuximab (400mg/m² then 250mg/m² weekly) and panitumumab (6.0mg/kg every two weeks). Chemotherapy included oxaliplatin, capecitabine, 5-fluorouracil, folinic acid, irinotecan, bevacizumab and leucovorin (doses varied, full details reported in the paper). Chemotherapy cycle length was two weeks in nine studies and over three weeks in one study.

The authors did not state how many reviewers assessed studies for inclusion.

Study quality was assessed using the Cochrane risk of bias tool for randomisation sequence generation, allocation concealment and reporting of outcome data.

The authors did not state how many reviewers assessed study quality.

Data on the proportion of patients with prespecified outcomes were extracted and used to calculate hazard ratios (HR) and odds ratios (OR), each with 95% confidence intervals (CI). Outcome data for patients with wild type KRAS and KRAS mutations were extracted separately. Study authors were contacted for additional data where necessary.

The authors did not state how many reviewers extracted data.

Pooled hazard ratios (progression-free and overall survival outcomes) and odds ratios (overall response rate) together with 95% confidence intervals were calculated using both fixed-effect and random-effects meta-analysis. Separate effect sizes were calculated for patients with wild type KRAS and KRAS mutations.

Subgroup analyses (for trials in the first and second line) investigated the line of treatment, antibody used, whether or not patients were previously untreated, chemotherapy regimen and choice of fluoropyrimidine.

Sensitivity analyses explored the robustness of results by including trials that compared chemotherapy (or supportive care) plus bevacizumab with or without anti-EGFR MAbs. Heterogeneity was assessed using Χ² test and Ι² statistic.

Ten randomised controlled trials were included: main analysis (eight RCTs, 6,974 patients randomised); sensitivity analysis (two RCTs, 1,808 patients randomised). Risk of bias was rated as low or unclear for progression-free survival in all trials.

Third line treatment: For patients with wild type KRAS, anti-EGFR MAbs treatment was associated with higher rates of progression-free survival (HR 0.43, 95% CI 0.35 to 0.52; Ι²=0%; two RCTs) and overall survival (HR 0.76, 95% CI 0.62 to 0.92; Ι²=88%; two RCTs) compared to standard treatment. There was no difference in overall survival between comparison groups when random-effects meta-analysis was used.

For patients with KRAS mutations there were no differences in rates of progression-free survival (HR 0.99, 95% CI 0.80 to 1.23; Ι²=0%; two RCTs) and overall survival (HR 1.00, 95% CI 0.80 to 1.26; Ι²=0%; two RCTs) between anti-EGFR MAbs and standard treatment groups.

First and second line treatment: For patients with wild type KRAS, anti-EGFR MAbs treatment was associated with higher rates of progression-free survival (HR 0.83, 95% CI 0.76 to 0.90; Ι²=62%; six RCTs), overall survival (HR 0.89, 95% CI 0.82 to 0.97; Ι²=24%; six RCTs) and best overall response (OR 1.77, 95% CI 1.52 to 2.06; Ι²=81%; six RCTs) compared to standard treatment.

For patients with KRAS mutations there were no differences in rates of progression-free survival (HR 1.06, 95% CI 0.96 to 1.17; Ι²=63%; six RCTs) and overall survival (HR 1.04, 95% CI 0.95 to 1.15; Ι²=0%; six RCTs) and odds of best overall response (OR 1.19, 95% CI 0.99 to 1.43; Ι²=0%) between anti-EGFR MAbs and standard treatment groups.

Sensitivity analysis: Analysis of bevacizumab in patients with wild type KRAS found that addition of bevacizumab to anti-EGFR MAbs was associated with poorer progression-free survival outcomes (HR 1.27, 95% CI 1.06 to 1.51; Ι²=0%; two RCTs).

For advanced colorectal cancer patients with wild-type KRAS there were clear benefits of anti-EGFR monoclonal antibodies in the third line and in the first and second line when used alongside infusional 5-fluorouracil based regimens. There was no benefit for patients with KRAS mutations.

The review addressed a clearly stated question. Eligible study designs, patients, treatments and outcomes were prespecified. Relevant databases and grey literatures sources were searched. The search period and search terms were not reported. It was unclear whether appropriate steps were taken to minimise likely error and bias during study selection, data extraction and quality assessment. Study quality was assessed using appropriate criteria and available evidence for primary outcome was reported to be of low risk or unclear risk of bias. Heterogeneity was assessed and results combined using appropriate meta-analysis. Adequate details of treatments and patients studied were reported.

The authors’ conclusions reflect the evidence presented. The conclusions are reliable but potential for reviewer error and bias should be borne in mind.

Practice: The authors stated that the absolute improvement in median progression-free survival from two to 4.7 months may be considered worthwhile by many clinicians and patients.

Research: The authors stated a need for that individual patient data meta-analyses to explore the impact of specific KRAS point mutations on treatment effect of anti-EGFR MAbs.

UK Medical Research Council.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.